Role of inoculum and mutant frequency on fosfomycin MIC discrepancies by agar dilution and broth microdilution methods in Enterobacteriaceae

Ballestero-Téllez, Mónica; Docobo-Pérez, Fernando; Rodríguez-Martínez, José Manuel; Conejo, M. Carmen; Ramos-Guelfo, María S.; Blázquez, Jesús; Rodríguez-Baño, Jesús; Pascual, Álvaro

doi:10.1016/j.cmi.2016.12.022

Cited by 42 publications

(31 citation statements)

References 21 publications

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“…The degree of comparability varied among species, and the differences tended to be one 2-fold dilution higher in broth, although there were examples of multiple fold increases. Ballestero-Tellez showed 86.4% categorical agreement when testing 81 E. coli isolates in broth microdilution with G-6-P compared to reference agar dilution and 51.1% categorical agreement for 139 K. pneumoniae isolates (22).…”

Section: Resultsmentioning

confidence: 94%

Evaluation of the Bactericidal Activity of Fosfomycin in Combination with Selected Antimicrobial Comparison Agents Tested against Gram-Negative Bacterial Strains by Using Time-Kill Curves

Flamm

Rhomberg

Lindley

et al. 2019

Antimicrob Agents Chemother

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The effects of combining fosfomycin with various antimicrobial agents were evaluated in vitro by broth microdilution checkerboard and time-kill kinetic studies. Checkerboard analyses were used to evaluate the following 30 Gram-negative isolates: 5 Pseudomonas aeruginosa, 5 Acinetobacter baumannii-Acinetobacter calcoaceticus species complex, and 20 Enterobacteriaceae isolates. No isolate exhibited antagonism when fosfomycin was tested in combination, and synergy was observed in more than 25% of the drug combinations tested. The most frequent instances of synergy occurred when testing fosfomycin with β-lactams. Two isolates of Pseudomonas aeruginosa, 2 of Klebsiella pneumoniae, and 1 of the A. baumannii-A. calcoaceticus species complex that exhibited synergy when fosfomycin was tested in combination were subjected to time-kill kinetic analyses for confirmation. Time-kill assays confirmed synergistic activity. These data indicated that combination therapy with fosfomycin may be beneficial.

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Section: Resultsmentioning

confidence: 94%

Evaluation of the Bactericidal Activity of Fosfomycin in Combination with Selected Antimicrobial Comparison Agents Tested against Gram-Negative Bacterial Strains by Using Time-Kill Curves

Flamm

Rhomberg

Lindley

et al. 2019

Antimicrob Agents Chemother

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“…Concerning the presence of double deletions, the ΔcyaA ΔglpT and ⌬ptsI ΔcyaA strains showed the highest reductions in the maximal growth rate in MH broth. We previously showed that FOS MIC determination may not be an accurate predictor of FOS efficacy (25,38). Susceptibility testing gives a measure of growth inhibition (MIC) under specific in vitro conditions.…”

Section: Discussionmentioning

confidence: 99%

Urinary Tract Conditions Affect Fosfomycin Activity against Escherichia coli Strains Harboring Chromosomal Mutations Involved in Fosfomycin Uptake

Martín-Gutiérrez

Docobo-Pérez

Rodríguez-Beltrán

et al. 2018

Antimicrob Agents Chemother

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The steps by which strains harboring mutations related to fosfomycin (FOS) resistance arise and spread during urinary tract infections (UTIs) are far from being understood. The aim of this study was to evaluate the effects of urine, pH, and anaerobiosis on FOS activity against a set of isogenic strains carrying the most prevalent chromosomal mutations conferring FOS resistance (Δ, Δ, Δ, and Δ), either singly or in combination. We also studied fosfomycin-resistant clinical isolates from patients with UTI. Our results demonstrate that urinary tract physiological conditions might have a profound impact on FOS activity against strains with chromosomal FOS resistance mutations. Specifically, acidic pH values and anaerobiosis convert most of the strains categorized as resistant to fosfomycin according to the international guidelines to a susceptible status. Therefore, urinary pH values may have practical interest in the management of UTIs. Finally, our results, together with the high fitness cost associated with FOS resistance mutations, might explain the low prevalence of fosfomycin-resistant variants in UTIs.

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“…Fosfomycin maintains in vitro activity against the vast majority of E. coli clinical strains, with reported susceptibility rates ranging between 94 and 99% (26)(27)(28). It is well acknowledged that resistance to fosfomycin can readily emerge spontaneously in vitro when conducting susceptibility testing (13,29,30). As fosfomycin use increases, the demand for susceptibility testing of this agent is expected to rise.…”

Section: Discussionmentioning

confidence: 99%

Frequency and Mechanisms of Spontaneous Fosfomycin Nonsusceptibility Observed upon Disk Diffusion Testing of Escherichia coli

et al. 2018

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Fosfomycin maintains activity against most clinical isolates, but the growth of colonies within the zone of inhibition around the fosfomycin disk is occasionally observed upon susceptibility testing. We aimed to estimate the frequency of such nonsusceptible inner colony mutants and identify the underlying resistance mechanisms. Disk diffusion testing of fosfomycin was performed on 649 multidrug-resistant clinical isolates collected between 2011 and 2015. For those producing inner colonies inside the susceptible range, the parental strains and their representative inner colony mutants were subjected to MIC testing, whole-genome sequencing, reverse transcription-quantitative PCR (qRT-PCR), and carbohydrate utilization studies. Of the 649 clinical isolates, 5 (0.8%) consistently produced nonsusceptible inner colonies. Whole-genome sequencing revealed the deletion of encoding hexose-6-phosphate antiporter in 4 of the inner colony mutants, while the remaining mutant contained a nonsense mutation in The expression of was absent in the mutant strains with deletion and was not inducible in the strain with the mutation, unlike in its parental strain. All 5 inner colony mutants had reduced growth on minimal medium supplemented with glucose-6-phosphate. In conclusion, fosfomycin-nonsusceptible inner colony mutants can occur due to the loss of function or induction of UhpT but are rare among multidrug-resistant clinical strains. Considering that these mutants carry high biological costs, we suggest that fosfomycin susceptibility of strains that generate inner colony mutants can be interpreted on the basis of the zone of inhibition without accounting for the inner colonies.

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Role of inoculum and mutant frequency on fosfomycin MIC discrepancies by agar dilution and broth microdilution methods in Enterobacteriaceae

Abstract: The higher inoculum used in the microdilution method enriched the initial inoculum with resistant subpopulations and could partially explain the fosfomycin MIC discrepancies with respect to the agar dilution method.

Cited by 42 publications

References 21 publications

Evaluation of the Bactericidal Activity of Fosfomycin in Combination with Selected Antimicrobial Comparison Agents Tested against Gram-Negative Bacterial Strains by Using Time-Kill Curves

Evaluation of the Bactericidal Activity of Fosfomycin in Combination with Selected Antimicrobial Comparison Agents Tested against Gram-Negative Bacterial Strains by Using Time-Kill Curves

Urinary Tract Conditions Affect Fosfomycin Activity against Escherichia coli Strains Harboring Chromosomal Mutations Involved in Fosfomycin Uptake

Frequency and Mechanisms of Spontaneous Fosfomycin Nonsusceptibility Observed upon Disk Diffusion Testing of Escherichia coli

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